SUMMARY Pulmonary arterial hypertension is a relentless disease characterized by vascular obliteration, right heart failure and death. Although there are ten FDA-approved therapies in three classes for PAH, none is curative and approximately 40% of patients are dead within 5 years of diagnosis. There is no established approach to identify patients who will respond to a specific therapy and many patients worsen while waiting for an effective therapy. The goals of this proposal are to improve outcomes in PAH using the concepts of precision medicine through an advanced genetics and ?Omics? approach incorporating transcriptomics, proteomics and metabolomics. Within cohorts of unselected PAH patients, there are two subsets with striking responses to therapy. One is a small subset that has a marked reduction in pulmonary artery pressure acutely in response to vasodilators and a dramatic long-term clinical response to calcium channel blocker therapy. We have recently published peripheral blood transcriptomic and genomic signatures of calcium channel blocker responsive patients differentiating them from non-responsive patients. The second subset is patients that have marked improvement with parenteral prostacyclin therapy. We and others have reported normalization of pulmonary arterial pressure in a subset of PAH patients treated with parenteral prostacyclin therapy. In preliminary data, we have identified clinical predictors of long-term survival in response to parenteral prostacyclin therapy and have found transcriptomic patterns that differentiate these patients. We have also identified variability in expression of the prostacyclin receptor in lymphoblastoids of control individuals and suppression of the receptor in PAH. We have preliminarily identified genetic variants that regulate prostacyclin receptor expression and that differentiate patients with good and poor responses to prostacyclin therapy. These data form the basis of our hypothesis that peripheral blood-derived genetic and Omic profiles identify correlates of prostacyclin responsiveness in PAH and can be exploited to understand mechanisms of drug efficacy and to optimize patient care. In this grant we propose to 1) understand genetic variation contributing to differential clinical response to prostacyclin therapy in PAH, 2) identify peripheral blood-derived Omic profiles to identify patients with durable clinical responses to parenteral prostacyclin therapy, 3) prospectively test our genetic and Omic profiles capacity to predict short-term responses to prostacyclin therapy in PAH clinically treated with PPs. The long term goals of this proposal are to better match a patient's unique biology to PP therapy, potentially improving survival in this highly morbid disease.